The transcription factor XBP-1 was identified as a key regulator of the mammalian unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response, which is activated by environmental stressors such as protein overload that require increased ER capacity (D. Ron, P. Walter (2007) Nat Rev Mol Cell Biol 8, 519). XBP-1 is activated by a post-transcriptional modification of its mRNA by IRE-1 alpha, an ER localizing proximal sensor of ER stress (M. Calfon et al. (2002) Nature 415, 92; H. Yoshida, et al. (2001) Cell 107, 881; X. Shen et al. (2001) Cell 107, 893). Upon ER stress, IRE-1 alpha induces an unconventional splicing of XBP-1 mRNA by using its endoribonuclease activity to generate a mature mRNA encoding an active transcription factor, XBP-1s, which directly binds to the promoter region of ER chaperone genes to promote transcription (A. L. Shaffer et al. (2004) Immunity 21, 81; A. H. Lee, et al. (2003) Mol Cell Biol 23, 7448; D. Acosta-Alvear et al. (2007) Mol Cell 27, 53). Mice deficient in XBP-1 display severe abnormalities in the development and function of professional secretory cells, such as plasma B cells and pancreatic acinar cells (N. N. Iwakoshi et al. (2003) Nat Immunol 4, 321; A. H. Lee, et al. (2005) Embo J 24, 4368). Secretion of immunoglobulin and zymogens from these cells is dramatically decreased in XBP-1 deficient mice, likely due to ER stress-induced apoptosis during development. XBP-1 is also required for embryonic liver development, although its function in the adult liver is unknown (A. M. Reimold et al. (2000) Genes Dev 14, 152).
The incidence of metabolic syndrome, a condition characterized by the constellation of central obesity, dyslipidemia, elevated blood glucose and hypertension, continues to rise in industrialized nations (G. A. Mensah et al. (2004) Cardiol Clin 22, 485). Dyslipidemia, manifested by elevated levels of plasma triglyceride (TG) and low density lipoprotein (LDL)-cholesterol and low levels of high density lipoprotein (HDL)-cholesterol is a risk factor for coronary artery disease (V. Bamba, D. J. Rader (2007) Gastroenterology 132, 2181; H. N. Ginsberg, Y. L. Zhang, A. Hernandez-Ono (2006) Obesity (Silver Spring) 14 Suppl 1, 41S). Increased de novo synthesis and secretion of lipids from the liver contributes significantly to the hepatic steatosis and dyslipidemia associated with type 2 diabetes (Bamba, D. J. Rader (2007) Gastroenterology 132, 2181; H. N. Ginsberg (2000) J Clin Invest 106, 453). Control of dyslipidemia with the statins, agents that target HMG CoA reductase, and with triglyceride lowering agents has resulted in measurable improvements in cardiovascular morbidity and mortality (J. D. Brunzell (2007) N Engl J Med 357, 1009). Hepatic lipid synthesis increases upon ingestion of excess carbohydrates, which are converted into TG, packaged into VLDL particles and transported to adipose tissue for energy storage (N. O. Davidson, G. S. Shelness (2000) Annu Rev Nutr 20, 169). Hepatic lipid metabolism is coordinated by multiple factors such as pancreatic hormones and serum glucose levels. In mammalian liver this transcriptional program is controlled by liver X receptor (LXR), sterol regulatory element-binding proteins (SREBPs) and ChREBP (S. W. Beaven, P. Tontonoz (2006) Annu Rev Med 57, 313; J. D. Horton, J. L. Goldstein, M. S. Brown (2002) J Clin Invest 109, 1125; K. Uyeda, J. J. Repa (2006) Cell Metab 4, 107; N. Mitro et al. (2007) Nature 445, 219) that directly or indirectly regulate the expression of critical enzymes involved in glycolytic and lipogenic pathways.
The further identification of molecular mechanisms involved in de novo lipogenesis would lead to identification of new drug targets and would provide methods of ameliorating dyslipidemia, steatosis, and steatohepatitis and, therefore, would be of great benefit.